PMID- 31657476
OWN - NLM
STAT- MEDLINE
DCOM- 20210205
LR  - 20210205
IS  - 1530-0277 (Electronic)
IS  - 0145-6008 (Print)
IS  - 0145-6008 (Linking)
VI  - 44
IP  - 1
DP  - 2020 Jan
TI  - Chronic Alcohol Consumption Enhances Skeletal Muscle Wasting in Mice Bearing 
      Cachectic Cancers: The Role of TNFalpha/Myostatin Axis.
PG  - 66-77
LID - 10.1111/acer.14221 [doi]
AB  - BACKGROUND: Chronic alcohol consumption enhances cancer-associated cachexia, 
      which is one of the major causes of decreased survival. The precise molecular 
      mechanism of how alcohol consumption enhances cancer-associated cachexia, 
      especially skeletal muscle loss, remains to be elucidated. METHODS: We used a 
      mouse model of chronic alcohol consumption, in which 20% (w/v) alcohol was 
      provided as sole drinking fluid, and Lewis lung carcinoma to study the underlying 
      mechanisms. RESULTS: We found that alcohol consumption up-regulated the 
      expression of MAFbx, MuRF-1, and LC3 in skeletal muscle, suggesting that 
      alcohol enhanced ubiquitin-mediated proteolysis and LC3-mediated autophagy. 
      Alcohol consumption enhanced phosphorylation of Smad2/3, p38, and ERK and 
      decreased the phosphorylation of FOXO1. These are the signaling molecules 
      governing protein degradation pathways. Moreover, alcohol consumption slightly 
      up-regulated the expression of insulin receptor substrate-1, did not affect 
      phosphatidylinositol-3 kinase, but decreased the phosphorylation of Akt and 
      mammalian target of rapamycin (mTOR), and down-regulated the expression of Raptor 
      and p70 ribosomal kinase S6 kinase, suggesting that alcohol impaired protein 
      synthesis signaling pathway in skeletal muscle of tumor-bearing mice. Alcohol 
      consumption enhanced the expression of myostatin in skeletal muscle, plasma, and 
      tumor, but did not affect the expression of myostatin in non-tumor-bearing mice. 
      In TNFalpha knockout mice, the effects of alcohol-enhanced expression of myostatin 
      and protein degradation-related signaling molecules, and decreased protein 
      synthesis signaling in skeletal muscle were abolished. Consequently, alcohol 
      consumption neither affected cancer-associated cachexia nor decreased the 
      survival of TNFalpha KO mice bearing cachectic cancer. CONCLUSIONS: Chronic alcohol 
      consumption enhances cancer-associated skeletal muscle loss through suppressing 
      Akt/mTOR-mediated protein synthesis pathway and enhancing protein degradation 
      pathways. This process is initiated by TNFalpha and mediated by myostatin.
CI  - (c) 2019 by the Research Society on Alcoholism.
FAU - Li, Yuanfei
AU  - Li Y
AD  - From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of 
      Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, 
      Washington.
AD  - Department of Oncology, (YL), The First Hospital of Shanxi Medical University, 
      Taiyuan, China.
FAU - Zhang, Faya
AU  - Zhang F
AD  - From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of 
      Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, 
      Washington.
FAU - Modrak, Samantha
AU  - Modrak S
AD  - From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of 
      Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, 
      Washington.
FAU - Little, Alex
AU  - Little A
AD  - From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of 
      Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, 
      Washington.
FAU - Zhang, Hui
AU  - Zhang H
AUID- ORCID: 0000-0002-6620-7173
AD  - From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of 
      Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, 
      Washington.
LA  - eng
GR  - R15 AA024284/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20191111
PL  - England
TA  - Alcohol Clin Exp Res
JT  - Alcoholism, clinical and experimental research
JID - 7707242
RN  - 0 (Mstn protein, mouse)
RN  - 0 (Myostatin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 3K9958V90M (Ethanol)
SB  - IM
MH  - Animals
MH  - Cachexia/chemically induced/metabolism
MH  - Carcinoma, Lewis Lung/*metabolism
MH  - Ethanol/administration & dosage/*toxicity
MH  - Female
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Muscle, Skeletal/drug effects/metabolism
MH  - Muscular Atrophy/*chemically induced/*metabolism
MH  - Myostatin/antagonists & inhibitors/*metabolism
MH  - Random Allocation
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors/*deficiency
PMC - PMC6980877
MID - NIHMS1056622
OTO - NOTNLM
OT  - Alcohol
OT  - Cancer-Associated Cachexia
OT  - Myostatin
OT  - Skeletal Muscle
OT  - TNFalpha
COIS- Disclosures: The authors have no financial conflicts of interest.
EDAT- 2019/10/28 06:00
MHDA- 2021/02/07 06:00
PMCR- 2021/01/01
CRDT- 2019/10/29 06:00
PHST- 2019/07/23 00:00 [received]
PHST- 2019/10/03 00:00 [revised]
PHST- 2019/10/23 00:00 [accepted]
PHST- 2019/10/28 06:00 [pubmed]
PHST- 2021/02/07 06:00 [medline]
PHST- 2019/10/29 06:00 [entrez]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.1111/acer.14221 [doi]
PST - ppublish
SO  - Alcohol Clin Exp Res. 2020 Jan;44(1):66-77. doi: 10.1111/acer.14221. Epub 2019 
      Nov 11.